1. Field of the Invention
This invention relates to new 17-allylamino-17-demethoxygeldanamycin (“17-AAG”) polymorphs, methods for making such new polymorphs, pharmaceutical formulations containing 17-AAG (especially formulations containing such new polymorphs), and methods for making and using such pharmaceutical formulations.
2. Description of Related Art
Geldanamycin belongs to the ansamycin natural product family, whose members are characterized by a macrolactam ring spanning two positions meta to each other on a benzenoid nucleus. Besides geldanamycin, the ansamycins include the macbecins, the herbimycins, the TAN-420s, and reblastatin.
Geldanamycin and its derivatives are the most extensively studied of the ansamycins. Although geldanamycin originally was identified as a result of screening for antibiotic activity, current interest resides primarily in its potential as an anticancer agent. It is an inhibitor of heat shock protein-90 (“Hsp90”), which is involved in the folding and activation of numerous proteins (“client proteins”), including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. The binding of geldanamycin to Hsp90 disrupts Hsp90-client protein interactions, preventing the client proteins from being folded correctly and rendering them susceptible to proteasome-mediated destruction. Among the Hsp90 client proteins are many mutated or overexpressed proteins implicated in cancer: p53, Bcr-Ab1 kinase, Raf-1 kinase, Akt kinase, Npm-Alk kinase, Cdk4, Cdk6, Wee1, HER2/Neu (ErbB2), and hypoxia inducible factor-1α (HIF-1α). However, the hepatotoxicity and poor bioavailability of geldanamycin have led to its discontinuation as a clinical candidate.
Nevertheless, interest persists in the development of geldanamycin derivatives or analogs having geldanamycin-like bioactivity, but with a more pharmaceutically acceptable spectrum of properties. Position 17 of geldanamycin has been an attractive focal point, chemically speaking, for the synthesis of geldanamycin derivatives because its methoxy group is readily displaced by a nucleophile, providing a convenient synthetic pathway to the 17-substituted-17-demethoxygeldanamycins. Structure-activity relationship (SAR) studies have shown that chemically and sterically diverse 17-substituents can be introduced without destroying antitumor activity. See, e.g., Sasaki et al., U.S. Pat. No. 4,261,989 (1981) (hereinafter “Sasaki”); Schnur et al., U.S. Pat. No. 5,932,566 (1999); Schnur et al., J. Med. Chem. 1995, 38 (19), 3806-3812; Schnur et al., J. Med. Chem. 1995 38 (19), 3813-3820; and Santi et al., U.S. Pat. No. 6,872,715 B2 (2005); the disclosures of which are incorporated by reference. The SAR inferences are supported by the X-ray crystal co-structure of the complex between Hsp90 and a geldanamycin derivative, showing that the 17-substituent juts out from the binding pocket and into the solvent (Jez et al., Chemistry & Biology 2003, 10, 361-368). The best-known 17-substituted geldanamycin derivative is 17-AAG, first disclosed in Sasaki and currently undergoing clinical trials. Another noteworthy derivative is 17-(2-dimethylaminoethyl)-amino-17-demethoxygeldanamycin (“17-DMAG”, Snader et al., U.S. Pat. No. 6,890,917 B2 (2005)), also in clinical trials.

In preparing a pharmaceutical formulation, consideration must be given to the possible existence of polymorphs of the drug being formulated. If they exist, they may differ in their pharmaceutically relevant properties, including solubility, storage stability, hygroscopicity, density, and bioavailability. One polymorph may more or less spontaneously convert to another polymorph during storage. As a result of such conversion, a formulation designed to deliver a particular polymorph may end up containing a different polymorph that is incompatible with the formulation. A hygroscopic polymorph may pick up water during storage, introducing errors into weighing operations and affecting handleability. A preparation procedure designed for use with a particular polymorph may be unsuitable for use with a different polymorph. Even if no interconversion occurs, one polymorph may be easier to formulate than another, making selection of the right polymorph critical. Thus, polymorph choice is an important factor in designing a pharmaceutical formulation. (As used herein, the term “polymorph” includes amorphous forms and non-solvated and solvated crystalline forms, as specified in guideline Q6A(2) of the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use).)
It is now known that 17-AAG is polymorphic. Sasaki originally disclosed a single form of 17-AAG melting at 212-214° C. Zhang et al., US 2005/0176695 A1 (2005) (hereinafter “Zhang”) and Mansfield et al., US 2006/0067953 A1 (2006) (hereinafter “Mansfield”) later reported that 17-AAG has a “high melt” form (mp 206-212° C.) and a “low-melt” form (mp 147-153° C.). The high melt form was the one initially obtained by Zhang and Mansfield in their syntheses 17-AAG and appears to be the same as the form reported by Sasaki, based on the closeness of the melting points. Zhang and Mansfield then reported preparing the low melt form from the high melt form by recrystallization from isopropanol. Mansfield includes X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) data for both forms and discloses oral pharmaceutical formulations made with them. Mansfield further discloses that the low melt form is actually a mixture of two polymorphs and that it is his preferred form for use in pharmaceutical formulations.
A difficulty in the preparation of pharmaceutical formulations of ansamycins such as geldanamycin and 17-AAG, especially for parenteral administration, lies in their very low water solubility. (17-DMAG, with its alkylamino group, is more soluble.) To date, various techniques have been disclosed for formulating 17-AAG or geldanamycin:    (a) Tabibi et al., U.S. Pat. No. 6,682,758 B1 (2004) discloses 17-AAG formulated in a water-miscible organic solvent, (c) a surfactant, and (d) water. The water miscible solvent can be dimethylsulfoxide (DMSO), dimethylformamide, ethanol, glycerin, propylene glycol, or polyethylene glycol. The surfactant can be egg phospholipid.    (b) Ulm et al., US 2006/0014730 A1 (2006) discloses an emulsion-based pharmaceutical formulation for ansamycins based on medium chain triglycerides, an emulsifying agent (e.g., phosphatidylcholine), and a stabilizer (e.g., sucrose).    (c) Ulm et al., US 2006/0148776 (2006) discloses a pharmaceutical composition comprising 17-AAG, an emulsifying agent, and an oil comprising both medium and long chain triglycerides.    (d) Zhong et al., US 2005/0256097 A1 (2005), discloses a formulation of 17-AAG in a vehicle comprising (i) a first component that is ethanol; (ii) a second component that is a polyethoxylated castor oil (e.g., Cremophor™); and (iii) optionally a third component that is selected from the group consisting of propylene glycol, PEG 300, PEG 400, glycerol, and combinations thereof.    (e) Isaacs et al., WO 2006/094029 A2 (2006), discloses a pharmaceutical formulation comprising 17-AAG dissolved in a vehicle comprising an aprotic, polar solvent and an aqueous mixture of long chain triglycerides.    (f) Mansfield discloses a pharmaceutical formulation for oral administration, comprising an ansamycin and one or more pharmaceutically acceptable solubilizers, with the proviso that when the solubilizer is a phospholipid, it is present in a concentration of at least 5% w/w of the formulation. Other solubilizers disclosed include polyethylene glycols of various molecular weights, ethanol, sodium lauryl sulfate, Tween 80, Solutol® HS15, propylene carbonate, and so forth. Both dispersion and solution embodiments are disclosed.    (g) Desai et al., WO 2006/034147 A2 (2006), discloses the use of dimethylsorbide as a solvent for formulating poorly water-soluble drugs such as ansamycins.
For poorly water soluble drugs such as 17-AAG, an alternative to solvent-based formulations are formulations in which very small particles—sometimes referred to as nanoparticles—of the drug are dispersed in a medium. See, generally, Wermuth, ed., The Practice of Medicinal Chemistry, 2nd Ed., pp. 645-646 (Academic Press 2003); Ribnow et al., Nature Reviews Drug Discovery 2004 3, 785-795; Peters et al., J. Antimicrobial. Chemotherapy 2000 45, 77-83; Itoh et al., Chem. Pharm. Bull. 2003 51 (2), 171-174; Burgess et al, AAPS Journal 2004, 6 (3), Article 20; Bosch et al., U.S. Pat. No. 5,510,118 (1996); De Castro, U.S. Pat. No. 5,534,270 (1996); and Bagchi et al., U.S. Pat. No. 5,662,883 (1997), the disclosures of which are incorporated herein by reference.
With specific reference to 17-AAG, an albumin-based nanoparticulate formulation has been disclosed: Tao et al., Am. Assoc. Cancer Res., 96th Annual Meeting (Apr. 16-20, 2005), abstract no. 1435. However, albumin may be pharmaceutically undesirable for an intravenous formulation. Mansfield, discussed supra, discloses a dispersion formulation of 17-AAG. Other patent documents generically reference the concept of making nanoparticle formulations of ansamycins (including, in certain cases, 17-AAG), but do not provide specific examples: Santi et al., U.S. Pat. No. 6,872,715 B2 (2005); Tian et al., U.S. Pat. No. 6,887,993 B1 (2005); Johnson, Jr., et al., US 2005/0020534 A1 (2005); Johnson, Jr., et al., US 2005/0020556 A1 (2005); Johnson, Jr., et al., US 2005/0020557 A1 (2005); Johnson, Jr., et al., US 2005/0020558 A1 (2005); Johnson, Jr., et al., US 2005/0026893 A1 (2005); Johnson, Jr., et al., US 2005/0054589 A1 (2005); and Johnson, Jr., et al., US 2005/0054625 A1 (2005); the disclosures of which are incorporated herein by reference.
The present invention provides new polymorphs of 17-AAG and pharmaceutical formulations made therefrom, in particular an especially desirable polymorph that is superior for the preparation of dispersion-based pharmaceutical formulations.